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Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans.

Publication ,  Journal Article
Kimbrel, NA; Ashley-Koch, AE; Qin, XJ; Lindquist, JH; Garrett, ME; Dennis, MF; Hair, LP; Huffman, JE; Jacobson, DA; Madduri, RK; Trafton, JA ...
Published in: JAMA psychiatry
February 2023

Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown.To identify novel, replicable genomic risk loci for SITB.This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022.SITB.A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P < 5 × 10-8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry-specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r > 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry.The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.

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Published In

JAMA psychiatry

DOI

EISSN

2168-6238

ISSN

2168-622X

Publication Date

February 2023

Volume

80

Issue

2

Start / End Page

135 / 145

Related Subject Headings

  • Veterans
  • TNF Receptor-Associated Factor 3
  • Suicidal Ideation
  • Proteins
  • Protein Serine-Threonine Kinases
  • Polymorphism, Single Nucleotide
  • Nucleotides
  • Male
  • Humans
  • Genome-Wide Association Study
 

Citation

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Kimbrel, N. A., Ashley-Koch, A. E., Qin, X. J., Lindquist, J. H., Garrett, M. E., Dennis, M. F., … Million Veteran Program Suicide Exemplar Workgroup, the International Suicide Genetics Consortium, the Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup, and the Veterans Affairs Million Veteran Program, . (2023). Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans. JAMA Psychiatry, 80(2), 135–145. https://doi.org/10.1001/jamapsychiatry.2022.3896
Kimbrel, Nathan A., Allison E. Ashley-Koch, Xue J. Qin, Jennifer H. Lindquist, Melanie E. Garrett, Michelle F. Dennis, Lauren P. Hair, et al. “Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans.JAMA Psychiatry 80, no. 2 (February 2023): 135–45. https://doi.org/10.1001/jamapsychiatry.2022.3896.
Kimbrel NA, Ashley-Koch AE, Qin XJ, Lindquist JH, Garrett ME, Dennis MF, et al. Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans. JAMA psychiatry. 2023 Feb;80(2):135–45.
Kimbrel, Nathan A., et al. “Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans.JAMA Psychiatry, vol. 80, no. 2, Feb. 2023, pp. 135–45. Epmc, doi:10.1001/jamapsychiatry.2022.3896.
Kimbrel NA, Ashley-Koch AE, Qin XJ, Lindquist JH, Garrett ME, Dennis MF, Hair LP, Huffman JE, Jacobson DA, Madduri RK, Trafton JA, Coon H, Docherty AR, Mullins N, Ruderfer DM, Harvey PD, McMahon BH, Oslin DW, Beckham JC, Hauser ER, Hauser MA, Million Veteran Program Suicide Exemplar Workgroup, the International Suicide Genetics Consortium, the Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center Workgroup, and the Veterans Affairs Million Veteran Program. Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans. JAMA psychiatry. 2023 Feb;80(2):135–145.

Published In

JAMA psychiatry

DOI

EISSN

2168-6238

ISSN

2168-622X

Publication Date

February 2023

Volume

80

Issue

2

Start / End Page

135 / 145

Related Subject Headings

  • Veterans
  • TNF Receptor-Associated Factor 3
  • Suicidal Ideation
  • Proteins
  • Protein Serine-Threonine Kinases
  • Polymorphism, Single Nucleotide
  • Nucleotides
  • Male
  • Humans
  • Genome-Wide Association Study